2-Amino-1,4-dihydropyridine derivatives

ABSTRACT

2-Amino-1,4-dihydropyridines bearing a carbonyl function in the 5-position and being optionally substituted by lower alkyl or phenyl in the 6-position, and the corresponding 2-amino1,4,5,6,7,8-hexahydro-5-oxoquinolines, which derivatives are further substituted by a carbonyl group in the 3-position and optionally substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5dicarboxylic acid 3,5-diethyl ester is a representative embodiment, are prepared through condensation of an ylideneacetoacetic acid ester and an amidine.

Meyer et a1.

1 1 Z-AMINO-l,4-DIHYDROPYRIDINE DERIVATIVES [76] Inventors: Horst Meyer;Friedrich Bossert;

Wulf Vater; Kurt Stoepel, all of c/o Bayer Aktiengesellschaft,Wuppertal-Elberfeld, Germany [22] Filed: Feb. 28, 1973 [21] Appl. No.:336,639

[30] Foreign Application Priority Data Mar. 6, 1972 Germany 2210674 [52]U.S. Cl. 260/294.9, 260/256.4 R, 260/256.4 C, 260/287 R, 260/289 R,260/294.8 C, 260/294.8 D, 260/294.8 F, 260/294.8 G, 260/295.5 R,260/295.5 A, 260/295.5 B, 260/296 R, 424/251, 424/258, 424/266 [51] Int.Cl. C07d 31/36, C07d 31/46 [58] Field of Search 260/294.8 F, 294.8 G,294.9, 260/295.5 R, 295.5 B

[561 References Cited UNITED STATES PATENTS 3,325,505 6/1967 Loev2611/2955 R 3,511,847 5/1970 Loev "2 60/2955 R 1 Feb. 18, 1975 PrimaryExaminer-Alan L. Rotman ABSTRACT 2-Amino-1,4-dihydropyridines bearing acarbonyl function in the 5-position and being optionally substituted bylower alkyl or phenyl in the 6-position, and the corresponding2-amino-1,4,5,6,7,8-hexahydro-5- oxoquinolines, which derivatives arefurther substituted by a carbonyl group in the 3-position and optionallysubstituted in the 4-position by lower alkyl, phenyl, substituted phenylor a heterocyclic group are antihypertensive agents and coronary vesseldilators. The compounds, of which 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid 3,5-diethy1 esteris a representative embodiment, are prepared through condensation of anylideneacetoacetic acid ester and an amidine.

35 Claims, N0 Drawings 1 Z-AMINO-1,4-DIHYDROPYRIDINE DERIVATIVESDETAILED DESCRIPTION The present invention pertains to 2-amino-l ,4-dihydropyridine derivatives, to processes for their production and useand to pharmaceutical compositions containing such compounds and usefulas antihypertensive agents and coronary vessel dilators.

In particular, the present invention pertains to compounds of theformula I: ii 2 R 3 R c I ca N na a wherein R is hydrogen; lower alkyl;lower alkenyl; lower alkynyl; phenyl; substituted phenyl in which thesubstituents are one to three members selected from the group consistingof lower alkyl,

lower alkoxy, halogeno, nitro, cyano, trifluoromethyl, azido,carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl, loweralkylthio or phenyl; naphthyl; or a heterocyclic ring selected from thegroup consisting of quinolyl, isoquinolyl, pyridyl, pyrimidyl, thenyl,furyl and pyrryl, said heterocyclic ring being unsubstituted orsubstituted by one or two members selected from the group consisting oflower alkyl, lower alkoxy and halogeno;

R, when taken independently, is hydrogen, lower alkyl, phenyl orpyridyl;

R when taken independently, is lower alkyl, lower alkoxy loweralkoxy(lower alkoxy), lower alkenyloxy, lower alkynyloxy, amino, loweralkylamino or di(lower alkyl)amino,

R and R when taken together are alkylene of 2 to 4 carbon atoms; and

R is lower alkyl, lower alkoxy, lower alkoxy(lower alkoxy), loweralkenyloxy, lower alkynyloxy, amino, lower alkylamino or di(loweralkyl)amino.

The term lower alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from 1 to 6 carbon atoms. Representative ofsuch lower alkyl groups are thus methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, neopentyl,tert.pentyl, hexyl, and the like.

The term lower alkenyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalethylenic unsaturation as, for example, vinyl, ally], isopropenyl,2butenyl, 3-mcthyl-2-butenyl, 2-pentenyl, 3-pentenyl, Z-hexenyl,4-hexenyl, and the like.

The term lower alkynyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalacetylenic unsaturation ecule through an ethereal oxygen atom as, forexample,

2 methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy andhexoxy.

The term lower alkylthio denotes a branched or straight hydrocarbonchain bound to the remainder of the molecule through a divalent sulfuras, for example, methylthio, ethylthio, propylthio, isopropylthio,hutylthio, and the like.

The term halogen denotes the substituents fluoro, chloro, bromo andiodo.

As indicated, the present invention also pertains to the physiologicallyacceptable non-toxic acid addition salts of these basic compounds. Suchsalts include those derived from organic and inorganic acids such as,without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methane sulphonic acid, acetic acid, tartaric acid,lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, embonic acid,enanthic acid, and the like.

According to the present invention, the foregoing compounds are preparedby reacting a dicarbonyl compound of the formula:

3 V R COCH CNH in which R is as herein defined. The condensationproceeds smoothly in good yields simply by heating the two components,generally in the presence of an inert organic solvent such as methanol,ethanol, propanol and similar alkanols, ethers such as dioxane anddiethyl ether, glacial acetic acid, pyridine, dimethylformamide,dimethylsulfoxide, acetonitrile and the like. The reaction is conductedat temperatures of from 20 to 250C, conveniently at the boiling point ofthe solvent, and while elevated pressure may be utilized, normalatmospheric pressure is generally satisfactory. The reactants areemployed in substantially equimolar amounts. The amidine reactant can beemployed as the free base or in the form of a salt such as thehydrohalide salts with the amidine being liberated from the salt throughtreatment with a basic agent such as an alkali metal alkoxide. Thedicarbonyl reagent can be utilized as such or generated in situ by thereaction of an aldehyde of the formula RCI-IO and a B-dicarbonylcompound of the formula RCOCH COR It is rather surprising that the abovedescribed condensation produces the desired compounds in such goodyields and with such high purity for while it is known that abenzylideneacetoacetic acid ester can be condensed with an aminocrotonic acid ester to yield a l,4-dinydropyridine (Knoevenagel, Ber.31, 743, [898), it would be expected from, for example, Silversmith, J.Org. Chem. 27, 4090 1952) that the addition of an amidine to anB-unsaturated keto compound would yield the dihydropyrimidine derivativerather than the dihydropyridine derivative.

Many of the dicarbonyl compounds utilized as one of the reactants areknown to the art and the others can either be generated in situ asherein described or prepared according to methods well known to the art,see for example Org. Reaction XV, 204 et seq. (1967). Typical of thisreactant are the following compounds:

benzylideneacetoacetic acid methyl ester,

ethylideneacetoacetic acid methyl ester, isopropylideneacetoacetic acidmethyl ester, 2-nitrobenzylideneacetoacetic acid methyl ester,2-nitrobenzylideneacetylacetone, benzylideneacetylacetone,3-nitrobenzylideneacetoacetic acid methyl ester,3-nitrobenzylideneacetoacetic acid propargyl ester,3-nitrobenzylideneacetoacetic acid allyl ester,3-nitrobenzylideneacetoacetic acid B-methoxyethyl ester,

3-nitrobcnzylideneacetoacetic acid B-ethoxyethyl ester,

3-nitrobenzylideneacetoacetic acid isopropyl ester,

3-nitrobenzylideneacetylacetone,

4-nitrobenzylideneacetylacetone, 4-nitrobenzylideneacetoacetic acidB-propoxyethyl ester,

4-nitrobenzylideneacetoacetic acid n-propyl ester,

3-nitro-6-chlorobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid ethyl ester,

2-cyanobenzylidenepropionylacetic acid ethyl ester,

3-cyanobenzylideneacetoacetic acid methyl ester,

3-nitro-4-chlorobenzylideneacetylacetone,

3-nitro-4-chlorobenzylideneacetoacetic acid t-butyl ester,

3-nitro-4-chlorobenzylideneacetoacetic acid methyl ester,2-nitro-4-methoxybenzylideneacetoacetic methyl ester,2-cyano-4-methylbenzylideneacetoacetic acid ethyl ester,

2-azidobenzylideneacetoacetic acid ethyl ester,

3-azidobenzylideneacetylacetone,

Z-methylmercaptobenzylideneacetoacetic acid isopropyl ester, I2-sulphinylmethylbenzylideneacetoacetic acid ethyl ester,

2-sulphonylbenzylidenemethylacetoacetic acid allyl ester,

4-sulphonylmethylbenzylideneacetoacetic acid ethyl ester,

naphth-l-ylideneacetoacetic acid methyl ester,

naphth-l-ylideneacetoacetic acid ethyl ester,

naphth-2-ylideneacetoacetic acid ethyl ester,2-ethoxynaphth-l-ylideneacetoacetic acid methyl ester,

Z-methoxynaphth-l-ylideneacetoacetic acid ethyl ester,

S-bromonaphth-l-ylideneacetoacetic acid methyl ester,

quinol-2-ylmethylideneacetoacetic acid methyl ester,

quinol-3-ylmethylidencacetoacetic acid methyl ester,

quinol-4-ylmcthylidcneacetoacetic acid ethyl ester,

quinol-8-ylmethylideneacetoacetic acid ethyl ester,

isoquinol-I-ylmethylideneacetoacetic acid methyl ester,

acid

isoquin0l-3-ylmethylideneacetoacetic acid methyl ester,

a-pyridylmethylideneacetoacetic acid methyl ester,

a-pyridylmethylideneacetoacetic acid ethyl ester,

a-pyridylmethylideneacetoacetic acid allyl ester,

a-pyridylmethylideneacetoacetic acid cyclohexyl ester,

B-pyridylmethylideneacetoacetic acid B-methoxyethyl ester,

y-pyridylmethylideneacetoacetic acid methyl ester,

6-methyl-a-pyridylmethylideneacetoacetic acid ethyl ester,

4,6-dimethoxypyrimid-5-y1methylideneacetoacetic acid ethyl ester,

then-2-ylmethylideneacetoacetic acid ethyl ester,

fur-2-ylmethylideneacetoacetic acid allyl ester,

pyrr-2-ylthylideneacetoacetic acid methyl ester,

nitrobenzylidenepropionylacetic acid ethyl ester,

a-pyridylmethylidenepropionylacetic acid ethyl ester,

a-pyridylmethylidenepropionylacetic acid methyl ester,

a-pyridylmethylideneacetylacetone,

2-, 3- or 4-methoxybenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-methoxybenzylideneacety[acetone,

2-methoxybenzylideneacetoacetic acid allyl ester,

2-methoxybenzylideneacetoacetic acid allyl ester,

Z-methoxybenzylideneacetoacetic acid propargyl ester,

Z-methoxybenzylideneacetoacetic acid B-methoxyethyl ester,

2-isopropoxybenzylideneacetoacetic acid ethyl ester,

3-butoxybenzylideneacetoacetic acid methyl ester,

3,4,5-trimethoxybenzylideneacetoacetic acid allyl ester,

Z-methylbenzylidenepropionylacetic acid methyl ester,

2-, 3- or 4-methylbenzylideneacetoacetic acid ethyl ester,

2-methylbenzylideneacetoacetic acid B-methoxyethyl ester,

2-methylbenzylideneacetoacetic acid B-propoxyethyl ester,

Z-methylbenzylideneacetylacetone,

3,4-dimethoxy-5-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-chl0robenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-fluorobenzylideneacetoacetic acid ethyl ester,

Z-fluorobenzylideneacetoacetic acid methyl ester,

3-chl0robenzylideneacetylacetone,

3-chlorobenzylidenepropionylacetic acid ethyl ester,

3-chlorobenzylideneacetoacetic acid ethyl ester,

2-chlorobenzylideneacetoacetic acid allyl ester,

2-, 3- or 4-trifluoromethylbenzylideneacetoacetic acid isopropyl ester,

3-trifluoromethylbenzylideneacetoacetic acid methyl ester,

2-carbethoxybenzylideneacetoacctic acid ethyl ester,

3-carbomethoxybenzylideneacetoacetic acid methyl ester,

4-carboisopropoxybenzylideneacetoacetic acid isopropyl ester, 1

4carbomethoxybenzylideneacetoacetic acid allyl ester,

3-nitrobenzylidenecyclohexane-l ,3-dione, and

3-nitrobenzylidenecycloheptane-1,3-dione.

The amidine reactants are similarly known or can be readily producedaccording to known methods, see for example McElvain et al., J.A.C,S.,73, 2760 (1951). Typical of these reactants are the following:

amidinoaoetic acid methyl ester,

amidinoacetic acid ethyl ester,

amidinoacetic acid n-propyl ester,

amidinoacetic acid isopropyl ester,

amidinoacetic acid cyclohexyl ester,

amidinoacetic acid B-methoxyethyl ester,

amidinoacetic acid a-ethoxyethyl ester,

arnidinoacetic acid B-ethoxyethyl ester, amidinoacetic acid propargylamidinoacetamide.

As noted above, the compounds of the present invention demonstrate theability to reduce blood pressure and to effect a dilation of thecoronary vessels. They can accordingly be used where either or both ofthese effects are desired. Thus upon parenteral, oral or sublingualadministration, the compounds produce a disester, and

tinct and long lasting dilation of the coronary vessels 7 which isintensified by a simultaneous nitritelike effect of reducing the load onthe heart. The effect on heart metabolism is thus one of energy saving.In addition, the compounds lower the blood pressure of normotonic andhypertonic animals and can thus be used as antihypertensive agents.These properties can be conveniently observed in well known laboratorymodels. Thus for example the coronary vessel dilation effect can beobserved by measuring the increase in oxygen saturation in the coronarysinus in the narcotized, heart catheterizcd dog, as shown in thefollowing table:

4-( 3-nitrophenyl)- l.4-dihydropyri' dine-3.5dicarbox \lie acid diethylester The hypotensive activity of the present compounds can be observedby measuring the blood pressure of hypertensivc rats followingadministration of the compounds. The following table demonstrates thedose which results in at least a 15 mm Hg reduction in blood pressure ofsuch animals:

Compound Dose (mg/kg) 2-amino-o-methyll-phenyll .4-

dihydropyridine'll .S-dicarboxylic -Continued Compound Dose (mg/kg) Thetoxicity of the compounds is remarkably low. Thus for example the toxicdose of 2-amino-6-methyl- 4-( 2-trifluoromethylphenyl )-l,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester in mice uponoral administration is greater than 1000 mg/kg.

In addition to the effect on blood pressure and coronary vessels, thecompounds also lower the excitability of the stimulus formation andexcitation conduction system within the heart so that anantifibrillation action is observed at therapeutic doses. The tone ofthe smooth muscle of the vessels is also greatly reduced. Thisvascular-spasmolytic action can be observed in the entire vascularsystem as well as in more or less isolated and circumscribed vascularregions such as the central nervous system. In addition, a strongmuscularspasmolytic action is manifested in the smooth muscle of thestomach, the intestinal tract, the urogenital tract and the respiratorysystem. Finally, there is some evidence that the compounds influence thecholesterol level and lipid level of the blood. These effects complementone another and the compounds are thus highly desirable.aspharmaceutical agents to be used in the treatment of hypertension andconditions characterized by a constriction of the coronary bloodvessels.

Pharmaceutical compositions for effecting such treatment will contain amajor or minor amount, eg from to 0.5%. of at least one 2-amino-l,4-dihydropyridine as herein defined in combination with a pharmaceuticalcarrier, the carrier comprising one or more solid, semi-solid or liquiddiluent, filler and formulation adjuvant which is nontoxic, inert andpharmaceutically acceptable. Such pharmaceutical compositions arepreferably in dosage unit form; Le. physically discrete units containinga predetermined amount of the drug corresponding to a fraction ormultiple of the dose which is calculated to produce the desiredtherapeutic response. The dosage units can contain one, two, three fouror more single doses or, alternatively, one-half, third or fourth of asingle dose. A single dose preferably contains an amount sufficient toproduct the desired therapeutic effect upon administration at oneapplication of one or more dosage units according to a predetermineddosage regimen, usually a whole, half,

third or quarter of the daily dosage administered once, twice, three offour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the daily dose will befrom about 0.001 to about 2 mg/kg, preferably 0.005 to 1.0 mg/kg, whenadministered parenterally and from about 0.1 to about 20 mg/kg,preferably 0.5 to 10 mg/kg, when administered orally. In some instancesa sufficient therapeutic effect can be obtained at lower doses while inothers, larger doses will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharamceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a la bricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mueilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themidicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixitsare prepared through the use of a nontoxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a nontoxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

The following examples will serve to further typify the nature of thepresent invention through the presentation of specific embodiments.These examples should not be construed as a limitation on the scope ofAppli cants invention since the subject matter regarded as the inventionis set forth in the appended claims.

EXAMPLE 1 Upon boiling a solution of 21.8 g of benzylideneacetoaceticacid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 150 mlof ethanol for 2 hours, 2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point164C (alcohol) is obtained.

Yield:67% of theory.

.EXAMPLE 2 Upon boiling a solution of 24.9 g of 2-nitrobenzylideneacetoacetic acid methyl ester and 13.0 g ofamidinoacetic acid ethyl ester in ml of ethanol for 1 hour,2-amino-6-methyl-4-(Z-nitrophenyl)-1,4- dihydropyridine-3,S-dicarboxylicacid 3-ethyl ester 5- methyl ester of melting point 168C (alcohol) isobtained.

Yield:59% of theory.

EXAMPLE 3 Upon boiling a solution of 24.8 g ofZ-methoxybenzylideneacetoacetic acid ethyl ester and 13.0 g ofamidinoacetic acid ethyl ester in ml of ethanol for 1 hour,2-amino-6-methyl-4-(2-methoxypheny1)-1,4-'

dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point170C (ethanol) is obtained. Yield:65% of theory.

EXAMPLE 4 Upon boiling a solution of 23.2 g ofZ-methylbenzylideneacetoacetic acid ethyl ester and 13.0 g ofamidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours,2-amino-6-methyl-4-(2-methylphenyl)-l,4-

dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point130C (ethanol) is obtained.

Yield:71% of theory.

EXAMPLE Upon boiling a solution of 24.3 g of 2-cyanobenzylideneacetoacetic acid ethyl ester and 13.0 g of amidinoaceticacid ethyl ester in 100 ml of ethanol for 2 hours,2-amino-6-methyl-4-(2-cyanophenyl)-1,4- dihydropyridine-3,S-dicarboxylicacid diethyl ester of melting point 208C (ethanol) is obtained.

Yield:547c of theory.

EXAMPLE 6 EXAMPLE 7 Upon boiling a solution of 12.6 g of 3-chlorobcnzylideneacetoacetic acid ethyl ester and 6.5 g of amidinoaceticacid ethyl ester in 100 ml of ethanol for 2 hours,2-amino-6-methyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point 157159C (ethanol) is obtained. Yield:62% of theory.

EXAMPLE 8 Upon boiling a solution of 13.2 g of4-methylmercaptobenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour,2-amino-6-methyl4-(4- methylmercaptophenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 165C (ethylacetate/petroleum ether) is obtained. Yield:49/r of theory.

EXAMPLE 9 Upon boiling a solution of 26.3 g of 3-nitrobenzylidcncacetoacetic acid ethyl ester and 13.0 g ofamidinoaceticacid ethyl ester in 200 ml of ethanol for 1 hour.2amino-6methyl-4-(3-nitrophenyl)-1,4 dihydropyridine 3.5-dicarboxylicacid diethyl ester of melting point 169C (ethanol) is obtained.

Yield:587r of theory.

EXAMPLE 10 Upon boiling a solution of 24.9 g of 3-nitrobenzylideneacetoacetic acid methyl ester and 13.0 g ofamidinoacetic acid ethyl ester in 180 ml of ethanol for 1 hour,2-amino-6-methyl-4-(3-nitrophenyl)-l,4- dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5 methyl ester of melting point 124C is obtained.Yield:59% of theory.

EXAMPLE 11 Upon heating a solution of 13.8 g of 3-nitrobenzylideneacetoacetic acid isopropyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours,2-amino-6-methyl-4-(3-nitrophenyl)- l.4-dihydropyridine-3,5dicarboxylicacid 3'ethyl 5- isopropyl ester of melting point 206 207C (alcohol) isobtained. Yield:62% of theory.

EXAMPLE 12 Boiling a solution of 10.9 g of 3-nitrobenzylideneacetoacetic acid propargyl ester and 5.2 g ofamidinoacetic acid ethyl ester in ml ofethanol for 1 hour yields2-amino-6-methyl-4-(3- nitrophenyl l ,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5-propargyl ester of melting point 181C (ethanol).

Yield:59% of theory.

EXAMPLE 13 Heating a solution of 14.6 g of 3-nitrobenzylideneacetoacetic acid B-methoxyethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in ml of ethanol for 1 hour yields2-amino-6-methyl-4-(3- nitrophenyl 1 ,4-dihydropyridine-3,5'dicarboxylicacid 3-ethyl ester S-B-methoxyethyl ester of melting point 179C (ethylacetate/petroleum ether). Yield:58% of theory.

EXAMPLE 14 Upon boiling a solution of 7.6 g of 3- nitrobenzaldehyde, 5.0g of acetylacetone and 6.5 g of amidinoacetic acid ethyl ester in 100 mlof ethanol for 2 hours, 2-amino-5'acetyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 217C(ethanol) is obtained.

Yield:48% of theory.

EXAMPLE 15 Upon boiling a solution of 14.2 g of 3-nitro-6-Chlorobenzylideneacetoacetic acid methyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour,2'amino-6-methyl-4-(3-nitro-6- chlorophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid 3-ethyl ester S-methyl esterofmelting point 124C (ethanol) is obtained.

Yield:73% of theory.

EXAMPLE 16 Upon boiling a solution of 10.4 g of 2-furfurylideneacetoacetic acid ethyl ester and 6.5 g of amidinoaceticacid ethyl ester in 100 m1 of ethanol for 2 hours,2-amino-6-methyl-4-(fur-2-yl)-1,4- dihydropyridine-3,S-dicarboxylic aciddiethyl ester of melting point 183C (isopropanol) is obtained. Yield:78%of theory.

EXAMPLE 17 Upon boiling a solution of 14.0 g of benzylidenebenzoylaceticacid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150 mlof ethanol for 2 hours, 2- amino-4,6-diphenyl-l ,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester of melting point 183C (ethanol) isobtained.

Yield:48% of theory.

EXAMPLE 18 Upon heating a solution of 15.6 g of ethylideneacetoaceticacid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 100 mlof ethanol for 2 hours, 2-amino-4,6-dimethyl-l,4-dihydropyridine-3,5dicarboxylic acid diethyl ester of melting point 140C (isopropanol)is obtained. Yield:59% of theory.

EXAMPLE 19 upon boiling a solution of 2.8 g of acetaldehyde, 5.6 g ofcyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 2 hours, 2- amino-4-methyl-l,4,5,6,7,8hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 236C(ethanol) is obtained. Yield:53% of theory.

EXAMPLE 20 Upon boiling a solution of 7.6 g of 3- nitrobenzaldehyde, 5.6g of cyclohexane-l ,3-dione and 6.5 g of amidinoacetic acid ethyl esterfor 1 hour, 2- amino-4-( 3-nitrophenyl)-l ,4,5,6,7,8-hexahydro*5-oxoquinolinc3-carboxylic acid ethyl ester of melting point 260C isobtained (alcohol/DMF). Yield: 61% of theory.

EXAMPLE 21 Upon boiling a solution of 7.1 g of 3- chlorobenzaldehyde,5.6 g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethylester in 150 ml of ethanol for 2 hours, 2-amino-4-(3-chlorophenyl)-1,4,5 ,6,7,S-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 266C (ethanol/DMF) is obtained.

Yield:66% of theory.

EXAMPLE 22 Upon boiling a solution of 5.3 g of pyridine-2- aldehyde, 5.6g of cyclhexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl ester in150 ml of alcohol for 3 hours,2amino-4-(a-pyridyl)-1,4,5,6,7,8-hexahydro- S-oxoquinoline'3-carboxylicacid ethyl ester of melting point 260C is obtained (alcohol).

Yield:46% of theory.

EXAMPLE 23 EXAMPLE 24 Upon heating a solution of 7.9 g of quinolin-4-aldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acidethyl ester in 150 ml of ethanol for 3 hours, 2-amino-4-(quinol-4-yl)-l,4,5 ,6,7,8- hexahydro-S-oxoquinolinecarboxylic acid 3-ethyl ester ofmelting point 260C (ethanol/DMF) is obtained. Yield:81% of theory.

EXAMPLE 25 Upon boiling a solution of 5.7 g of 4,6-dimethoxypyrimidin--aldehyde, 3.8 g of cyclohexane- 1.3-dioncand 4.4 gof aniidinoacetic acid ethyl ester in 80 ml of ethanol for 8 hours,2-amino-4-(4,6- dimcthoxypyrimid-5-yl)-l.4,5.6.7.8-hcxahydro-5-oxoquinoline-3-carboxy1ic acid ethyl ester of melting point 273C(alcohol) is obtained. Yield:65% of theory.

EXAMPLE 26 Upon boiling a solution of 6.3 g of l-naphthaldehyde, 4.5 gof cyc1ohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in150 ml of ethanol for 2 hours, 2-amino-4-(naphth-1-y1)-l,4,5,6,7,8-hexahydro-5- oxoquinoline-3-carboxylic acid ethyl ester 01melting point 279C (ethanol/DMF) is obtained.

Yield:64% of theory.

EXAMPLE 27 Upon heating a solution of 6.3 g of isoquinolin-laldehyde,4.5 g of cyclohexane-l,3-dione and 5.2 g of amidinoacetic acid ethylester in ml of ethanol for 2 hours, 2-amino-4-(isoquinol-1-yl)-l,4,5,6.7,8- hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 272C (ethanol) is obtained.

EXAMPLE 28 Upon heating a solution of 4.8 g of 6-methylpyridin-Z-aldehyde, 4.5 g of cyclohexane-l,3-dione and 5.2 g of amidinoaceticacid ethyl ester in ml of ethanol for 8 hours,2-amino-4-(6-methylpyrid-2-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 260C (ethanol/DMF) is obtained. Yield:46% of theory.

EXAMPLE 29 Upon boiling a solution of 13.3 g of 3-nitrobenzylideneacetoacetic acid ethyl ester and 5.1 g ofamidinoacetamide in ml of ethanol for 2 hours,2-amino-6-methyl-5-carbethoxy-4-( 3-nitrophenyl1,4-dihydropyridine-3-carboxylic acid amide of melting point 260C(alcohol) is obtained.

Yield:52% of theory.

EXAMPLE 30 Upon heating a solution of 6.5 g of 2- cyanobenzaldehyde, 5.6g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 5 hours, 2-amino-4-(2-cyanophenyl)-l,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point C (ethanol) is obtained.

Yield:49% of theory.

EXAMPLE 31 Upon heating a solution of 26.3 g of 3-nitrobenzylideneacetoacetic acid ethyl ester and 14.4 g of amidinoaceticacid isopropyl ester in 250 ml of ethanol for 2 hours,2amino-6-methyl-4-(3-nitrophenyl) l,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester S-ethyl ester of melting point 6C (ethanol) isobtained.

Yield:77% of theory.

EXAMPLE 32 Heating a solution of 14.3 g of2-trifluoromethylbenzylideneacetoacetic acid ethyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 150 ml of ethanol for 1 houryields 2-amino-6-methyl-4-( 2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-

dicarboxylic acid 3-isopropyl ester S-ethyl ester of melting point 106C.Yie1d:49% of theory.

EXAMPLE 33 EXAMPLE 34 Upon boiling a solution of 12.2 g of 2-cyanobenzylideneacetoacetic acid ethyl ester and 7.2 g of amidinoaceticacid isopropyl ester in 200 ml of ethanol for 1 hour,2-amino-6-methyl-4-(2-cyanophenyl)- l,4-dihydropyridine-3,S-dicarboxylicacid 3-isopropyl ester 5-ethy1 ester of melting point 200C (isopropanol)is obtained.

Yield:58% of theory.

EXAMPLE 35 Upon heating a solution of 12.5 g of 3-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g of amidinoaceticacid isopropyl ester in 150 ml of ethanol for 2 hours,2-amino-6-methyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3,5'dicarboxylicacid 3-isopropyl ester S-methyl ester of melting point 167C (ethanol) isobtained.

Yield:82% of theory.

EXAMPLE 36 Upon heating a solution of 11.0 g of 2-trilluoromethyl-4-nitrobcnzaldehyde, 5.6 g of cyclohexane-1,3-dione and6.5 g of amidinoacetic acid ethyl ester in 250 ml of ethanol of 2 hours,2-amin0-4- (2-tri1luoromethyl-4-nitrophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point264C (ethanol) is obtained. Yield:62% of theory.

EXAMPLE 37 Heating 21 solution of 13.2 g of 3-nitrobenzylideneacetoacetic acid ethyl ester and 7.2 g of amidinoaceticacid n-propyl ester in 200 ml of ethanol for 2 hours yields2-amino-6-methyl-4-(3- nitrophenylyl ,4dihydropyridine-3,S-dicarboxylicacid 3-n-propyl ester 5-ethyl ester of melting point 168C (ethanol).

Yield:797r of theory.

EXAMPLE 38 Boiling a solution of 8.5 g of 6-nitroveratraldehyde, 4.0 gof cyclohexane-l,3-dione and 5.2 g of amidinoacetic acid ethyl ester in150 ml of ethanol for 1 hour yields2-amino-4-(2-nitro-4,5-dimethoxyphenyl)- l,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of meltingpoint 261C (ethanol). Yield:52% of theory.

EXAMPLE 39 Boiling a solution of 13.2 g of 3-nitrobenzylideneacetoacetic acid ethyl ester and 8.0 g of amidinoaceticacid B-methoxyethyl ester in 200 ml of ethanol for 2 hours yields2-amino-6-methy1-4-(3- nitrophehyl)-1,4-dihydropyridine-3,S-dicarboxylicacid 3-(i3-methoxyethyl) ester S-ethyl ester of melting point 174C.

Yield:59% of theory.

EXAMPLE 40 Upon heating a solution of 6.1 g of biphenyl-2- aldehyde, 3.8.g of cyclohexane-l,3-dione and 5.1 g of amidinoacetic acid ethyl esterin ml of ethanol for 1 hour, 2-amino-4-(biphenyl-2-yl)-1,4,5,6,7,8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester of melting point248C (ethanol) is obtained. Yield:45% of theory.

EXAMPLE 41 Boiling a solution of 13.4 g of (lnaphthylidene)acetoaceticacid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 mlof ethanol for 8 hours yields 2-amino-6-methyl-4-(1-naphthy1)-1,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point174C (ethanol).

Yield:62% of theory.

EXAMPLE 42 Upon heating a solution of l 1.5 g of 2-cyanobenzylideneacetoacetic acid methyl ester and 7.2 g of amidinoaceticacid isopropyl ester in 100 m1 ofethanol for 6 hours,2-amino-6-methyl-4-(2- cyanophenyl )-l,4-dihydropyridine-3,S-dicarboxylic acid 3-isopropyl ester S-methylester of melting point 211C (ethanol) is obtained.

Yield:72% of theory.

EXAMPLE 43 Upon boiling a solution of 11.5 g of 2-cyanobenzylideneacetoacetic acid methyl ester and 6.5 g of amidinoaceticacid ethyl ester in 100 ml of ethanol for 8 hours,2-amino-6-methyl-4-(2-cyanophenyl)-l,4- dihydropyridine-3,S-dicarboxylicacid 3-ethyl ester 5- methyl ester of melting point 224C (ethanol) isobtained.

Yield:66% of theory.

EXAMPLE 44 Upon boiling a solution of 14.8 g of2-phenylbenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours,2-amino-6-methyl-4-(biphenyl-Z-yl)-1,4- dihydropyridine-3,S-dicarboxylicacid ethyl ester of melting point 182C (ethanol) is obtained.

Yield:4l% of theory.

EXAMPLE 45 Upon heating a solution of 12.5 g of 3-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g of amidinoaceticacid n-propyl ester in 100 ml of ethanol for 6 hours,2-amino-6-methyl-4-(3-nitropheny1)- 1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-methyl ester of melting point C (ethanol) isobtained.

Yield:69% of theory.

EXAMPLE 46 Upon heating a solution of 12.2 g of (2-thenylidene)acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acidethyl ester in 100 m1 of ethanol for 15 4 hours,2-amino-6-methyl-4-(2-thenyl)-1,4- dihydropyridine-3,S-dicarboxylic aciddiethyl ester of melting point 170C (ethanol) is obtained. Yield:73% oftheory.

EXAMPLE 47 Upon heating a solution of 10.9 g of benzylideneacetoaceticacid dimethylamide and 5.0 g of amidinoacetamide in 100 ml of ethanolfor 8 hours, 2- amino-6-methyl-4-phenyl-5-(N,N- dimethylaminocarbonyl)-1,4-dihydropyridine-3- carboxylic acid amide of melting point 236C(ethanol) is obtained.

Yield:50% of theory.

EXAMPLE 48 Heating a solution of 10.9 of benzylideneacetoacetic aciddimethylamide and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofmethanol for 6 hours yields 2-amino-6methyl-4-phenyl-1,4-dihydropyridine-3,5- dicarboxylic acid3-ethyl ester 5-(N,N-dimethylamide) of melting point 230C (alcohol).

Yield:61% of theory.

EXAMPLE 49 Boiling a solution of 13.2 g of 2-nitrobenzylideneacetoacetic acid ethyl ester and 7.2 g of amidinoaceticacid isopropyl ester in 100 ml of ethano] for 6 hours yields2-amino-6-methyl-4-(2- nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylicacid 3-isopropyl ester S-ethyl ester of melting pont 139C (isopropanol).

Yield: 39% of theory.

EXAMPLE 50 Boiling a solution of 13.2 g of 2-nitrobenzylideneacetoacetic acid ethyl ester and 6.5 g of amidinoaceticacid ethyl ester in 100 ml of ethanol for 6 hours yields2-amino-6-methyl-4-(2-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 159C (ethanol).

Yield:52% of theory.

EXAMPLE 51 Upon heating a solution of 12.5 g of 2-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g of amidinoaceticacid isopropyl ester in 100 ml of ethanol for 8 hours,2-amino-6-methyl-4-(2-nitrophenyl)- 1,4-dihydropyridine-3,S-dicarboxylicacid 3-isopr0pyl ester S-methyl ester of melting point 203C(isopropanol) is obtained.

Yield: 50% of theory.

EXAMPLE 52 Upon heating a solution of 12.2 g of 2-cyanobenzylideneacetoacetic acid ethyl ester and 7.2 g of amidinoaceticacid n-propyl ester in 100 ml of ethanol for 8 hours,2-amino-6-methyl-4-(2-cyanopheny1)- 1,4-dihydropyridine-3,S-dicarboxylicacid 3-n-propyl ester 5-ethyl ester of melting point 182C (ethanol) isobtained.

Yield:62% of theory.

EXAMPLE 53 Upon heating a solution of 13.9 g of 3-nitrobcnzylidencacetoucetic acid isopropyl ester and 7.2 g ofamidinoacetic acid n-propyl ester in 101) ml of ethanol for 6 hours, 2amino-6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylicacid 3-n-propyl ester 5-isopropy1 ester of melting point 199C(isopropanol) is obtained.

Yield:% of theory.

EXAMPLE 54 Heating a solution of 6.5 g of 3-cyanobenzaldehyde, 5.6 g ofcyclohexane-l ,3-dione and 6.5 g of amidinoacetic acid ethyl ester in mlof ethanol for 6 hours yields 2-amino-4-(3-cyanophenyl)-1,4,5,6,7,8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester of melting point262C (ethanol/dimethylformamide).

Yield:56% of theory.

EXAMPLE 55 Upon heating a solution of 9.3 g of 3- bromobenzaldehyde, 5.6g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 8 hours, 2-amino-4-(3-bromophenyl)-l,4,5,6,7,8-hexahydro-5-oxoquin0line-3-carboxylic acid ethyl ester ofmelting point 255C (ethanol) is obtained.

Yie1d:44% of theory.

EXAMPLE 56 Upon boiling a solution of 9.3 g of 2' bromobenzaldehyde, 5.6g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 6 hours, 2-amino-4-(2-bromophenyl)-l,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 245C (ethanol) is obtained.

Yield:46% of theory.

EXAMPLE 57 Upon heating a solution of 8.9 g of 3-carbethoxybenzaldehyde,5.6 g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethylester inlOO ml of ethanol for 4 hours,2-amino-4-(3-carbethoxyphenyl)-l,4,5,6,7,8-hexahydro-Soxoquinoline-3-carboxylic acid ethyl ester of melting point234C (ethanol) is obtained. Yield:54% of theory.

EXAMPLE 58 ll ii 2 R a a RCI\I I/CR 1/ N \Nflz K wherein naphthyl,phenyl or phenyl substituted with from one to three substituentsselected from the group consisting of lower alkyl, lower alkoxy,halogeno, nitro, cyano, trifluoromethyl, azido, carbo(lower alkoxy),lower alkylsulfonyl, lower alltylsulfinyl, lower alkylthio or phenyl.

amino6-methyl-4-( 2-nitrophenyl )-l ,4- dihydropyridine-3,S-dicarboxylicacid diethyl ester.

amino-6-methyl-4-( B-nitrophenyl )-l ,4-dihydropyridine-3,S-dicarboxylic acid 3-ethyl ester-5- methyl ester.

amino-6-methyl-4-( 3-chlorophenyl l ,4- dihydropyridine-3,S-dicarboxylicacid diethyl ester.

lower alkyl or phenyl.

3. A compound according to claim 2 wherein R is 4. The compoundaccording to claim 3 which is 2- 2O amino-6-methyl-4-phenyl-l,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester.

5. The compound according to claim 3 which is 2- 6. The compoundaccording to claim 3 which is 2- amino-6-methyl-4(Z-methoxyphenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester.

7. The compound according to claim 3 which is 2- 3O amino-6-methyl-4-(2-cyanophenyl l ,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester.

8. The compound according to claim 3 which is 2- 9. The compoundaccording to claim 3 which is 2- amino-6-methyl-4-( 3-nitrophenyl )-l,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester.

ill). The compound according to claim 3 which is 2- ll. The compoundaccording to claim 3 which is 2- T2. The compound according to claim 3which is 2- amino-6-methyl-4-( Z-nitrophenyl )-l ,4-dihydropyridine3,S-dicarboxylic acid 3-ethyl ester 5- methyl ester.

13. The compound according to claim 3 which is 2- amino-6-methyl-4-(2-methylphenyl)-I ,4- dihydropyridine-3,5-dicarboxylic acid diethylester.

M. The compound according to claim 3 which is 2- H5. The compoundaccording to claim 3 which is 2-amino-6-methyl-4-(4-methylmercaptophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester.

T6. The compound according to claim 3 which is 2- amino-6-methyl-4-(3-nitrophenyl)-l ,4- dihydropyridine-3,S-dicarboxylic isopropyl ester.

acid 3-ethyl 5- H7. The compound according to claim 3 which is 2- 18.The compound according to claim 3 which is 2- amino-6-methyl-4-(3-nitro-6-chlorophenyl)- l ,4- dihydropyridine-3,S-dicarboxylic acid3-ethyl ester 5- methyl ester.

19. The compound according to claim 3 which is 2- amino-4,6-diphenyll,4-dihydropyridine-3,5- dicarboxylic acid ethyl ester.

20. The compound according to claim 3 which is 2- amino-6-methyl-4-(3-nitrophenyl l ,4- dihydropyridine-3,S-dicarboxylic acid 3-isopropylester 5 ethyl ester.

21. The compound according to claim 3 which is 2-amino-6-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine3,S-dicarboxylicacid 3-isopropyl ester 5- ethyl ester.

22. The compound according to claim 3 which is 2- amino-6-methyl-4-(3-nitrophenyl l ,4- dihydropyridine-3,S-dicarboxylic acid diisopropylester.

23. The compound according to claim 3 which is 2- amino-6-methyl-4-(2-cyanophenyl )-l ,4- dihydropyridine-3,S-dicarboxylic acid 3-isopropylester S-ethyl ester.

24. The compound according to claim 3 which is 2- amino-6-methyl-4(3-nitrophenyl)-l ,4- dihydropyridine-3,5-dicarboxylic acid 3-isopropylester S-methyl ester.

25. The compound according to claim 3 which is 2- amino-6-methyl-4-(3-nitrophenyl)- l ,4- dihydropyridine-3,5-dicarboxylic acid 3-n-propylester 5-ethyl ester.

26. The compound according to claim 3 which is 2-amino-6-methyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,S-dicarboxylic3-(B- methoxyethyl) ester S-ethyl ester.

27. The compound according to claim 3 which is 2- amino-6-methyl-4-(l-naphthyl)-l ,4-dihydropyridine- 3,5-dicarboxylic acid diethyl ester.

28. The compound according to claim 3 which is 2- amino-6-methyl-4-(2-cyanophenyl )-l ,4- dihydropyridine-3,S-dicarboxylic acid 3-isopropylester S-methyl ester.

29. The compound according to claim 3 which is 2- amino-6-methyl-4-(2-cyanophenyl )-l ,4- dihydropyridine-3,S-dicarboxylic acid 3-ethylester 5- methyl ester.

30. The compound according to claim 3 which is 2-amino-6-methyl-4-(biphenyl-2-yl)-1,4- dihydropyridine'3,S-dicarboxylicacid ethyl ester.

31. The compound according to claim 3 which is 2- amino-6-methyl-4-(3-nitrophenyl )-l ,4- dihydropyridine-3,S-dicarboxylic acid 3-n-propylester S-methyl ester.

32. The compound according to claim 3 which is 2- amino-6-methyl-4-(2-nitrophenyl )-l ,4- dihydropyridine-3,S-dicarboxylic acid 3-isopropylester S-ethyl ester.

33. The compound according to claim 3 which is 2- amino-6-methyl-4-(2-nitrophenyl )-l ,4- dihydropyridine-3,S-dicarboxylic acid 3-isopropylester 5-methyl ester.

34. The compound according to claim 3 which is 2- amino-6-methyl-4-(2-cyanophenyl )-l ,4- dihydropyridine-3.S-dicarboxylic acid 3-n-propylester S-ethyl ester.

35. The compound according to claim 3 which is 2- amino-6-methyl-4-(3-nitrophenyl)-l ,4- dihydropyridine-3,S-dicarboxylic acid 3-n-propylester 5-isopropyl ester.

acid

UNITED STATES PATENT OFFICE CERT IFICATE OF CORRECTION PATENT N0 386733DATED February 18, 1975 INVENTORtS) HORST MEYER et 31 It is certifiedthat error appears in the aboveidentified patent and that said LettersPatent are hereby corrected as shown below:

Change the German priority application number to rrflad 221967-Jt- Claim3 line 2, change "napnthyl; pnenyl or phenyl" ts read. naphthyl; phenyl;phenyl change the East line of claim 3 to read sulfonyl, lsweratkylsulfinyl and lower alkyltnio; or biphenyl Signed and sealed this17th day of June 1975.

C. IL'XRSHALL "AP-TN RUTH C. IZASOEI Commissioner oi? Patents [attestingOfficer and Trademarks s. h ...J

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 whereinR1 is lower alkyl or phenyl.
 3. A compound according to claim 2 whereinR is naphthyl, phenyl or phenyl substituted with from one to threesubstituents selected from the group consisting of lower alkyl, loweralkoxy, halogeno, nitro, cyano, trifluoromethyl, azido, carbo(loweralkoxy), lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio orphenyl.
 4. The compound according to claim 3 which is2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 5. The compound according to claim 3 which is2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 6. The compound according to claim 3 which is2-amino-6-methyl-4-(2-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 7. The compound according to claim 3 which is2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 8. The compound according to claim 3 which is2-amino-6-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester.
 9. The compound according to claim 3which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 10. The compound according to claim 3 which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester-5-methyl ester.
 11. The compound according to claim 3which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester-5-( Beta -methoxyethyl) ester.
 12. The compoundaccording to claim 3 which is2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5-methyl ester.
 13. The compound according to claim 3which is2-amino-6-methyl-4-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 14. The compound according to claim 3 which is2-amino-6-methyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 15. The compound according to claim 3 which is2-amino-6-methyl-4-(4-methylmercaptophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester.
 16. The compound according to claim 3which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl 5-isopropyl ester.
 17. The compound according to claim 3which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5-propargyl ester.
 18. The compound according toclaim 3 which is2-amino-6-methyl-4-(3-nitro-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester.
 19. The compoundaccording to claim 3 which is2-amino-4,6-diphenyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethylester.
 20. The compound according to claim 3 which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-ethyl ester.
 21. The compound according toclaim 3 which is2-amino-6-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine3,5-dicarboxylic acid 3-isopropyl ester 5-ethyl ester.
 22. The compoundaccording to claim 3 which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diisopropyl ester.
 23. The compound according to claim 3 which is2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-ethyl ester.
 24. The compound according toclaim 3 which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-methyl ester.
 25. The compound according toclaim 3 which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-ethyl ester.
 26. The compound according to claim3 which is2-amIno-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-( Beta -methoxyethyl) ester 5-ethyl ester.
 27. The compoundaccording to claim 3 which is2-amino-6-methyl-4-(1-naphthyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 28. The compound according to claim 3 which is2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-methyl ester.
 29. The compound according toclaim 3 which is2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5-methyl ester.
 30. The compound according to claim 3which is2-amino-6-methyl-4-(biphenyl-2-yl)-1,4-dihydropyridine-3,5-dicarboxylicacid ethyl ester.
 31. The compound according to claim 3 which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-methyl ester.
 32. The compound according toclaim 3 which is2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-ethyl ester.
 33. The compound according toclaim 3 which is2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester 5-methyl ester.
 34. The compound according toclaim 3 which is2-amino-6-methyl-4-(2-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-ethyl ester.
 35. The compound according to claim3 which is2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-isopropyl ester.